Breast cancer diagnosed at an early stage is usually cured, but a significant percentage of patients will experience a metastatic recurrence that is not curable despite advances in therapy. The very long interval of time to recurrence seen in some cases suggests the phenomenon of cancer dormancy, but very little is known about the physiology of metastasis and the determinants that govern the occurrence and timing of clinical recurrence. We have demonstrated the presence of circulating tumor cells (CTCs) in patients with prior breast cancer who are 7-22 years post-mastectomy and who have no evidence of disease (NED), thus very likely to be in a tumor dormancy state. Our preliminary data from 40 of these patients indicate that 18 have CTCs, using very stringent criteria including cytomorphology, immunophenotyping and aneusomy. Nineteen normal women had no cells in the blood that met the criteria for CTCs. All personnel involved in the procedures /interpretation were blinded. The procedure involved immunomagnetic purification followed by immunofluorescence analysis for CTCs on slides using the above criteria. From preliminary observations, the half-life of CTCs was estimated to be only several hours. Since 13 of the patients with CTCs are 13- 22 years post mastectomy with NED and the half-life of the CTCs is so short, we postulate that dormancy in breast cancer can represent a precise balance between cell replication and cell death. We plan to extend our studies to a large number (150) of patients 8 or more years after removal of a breast carcinoma with NED, a control group (50) of age-matched normal women, and 50 patients with metastatic breast carcinoma. The CTCs will be studied in-depth by counting, immunophenotyping and genotyping to determine if the CTCs from the dormant group differ from CTCs in metastatic breast carcinomas and whether a relapse is developing. The initial tumors and their treatments in the dormant vs. the metastatic tumor group will also be analyzed for differences. Exploratory experiments to determine the mechanisms responsible for this precise balance will be done. Providing concrete evidence of a dormancy state and being able to characterize the kinetics, genotype and phenotype of CTCs and the mechanisms by which they are regulated have enormous implications in cancer control and treatment.